4-methyl testosterone compounds



nited States No Drawing. Application January 29, 1957 The presentinvention relates to cyclopentanophenanthrene derivatives and to aprocess for the production thereof.

More particularly the present invention relates to novel androgenichormones which are 4-alkyl and 4-aralkyl derivatives of testosterone,dihydrotestosterone, 17-lower alkyl testosterone and 17-lower alkyldihydrotestosterone. The novel useful androgens of' the presentinvention difier substantially in their characteristics from the samecompounds without a substituent in C-4 especially in. that they have ahigher anabolic-androgenic ratio. For example in the standard rat assay4-methy1testosterome had 40% of the androgenic activity and 120% of themyotropic (anabolic) activity of testosterone.

In accordance with the present invention it has been discovered that thenovel compounds just described may be prepared by reactingetiocholanolone (testan-l7fi-ol-3- one) with ethyl oxalate in thepresence of sodium hydride; to give the corresponding 4-ethoxyglyoxylderivative. This last derivative upon treatment with an alkyliodida oran aralkyl iodide gave the 4-a1kyl or aralkyl-4'-ethoxy'-glyoxal-etiocholan-17-B-ol-3-one derivative and treatment with sodiumethoxide gave the corresponding 4-alkyl or; aralkyl etiocholan compound.Monobromination and dr hydrobromination gave the corresponding novel A drivatives and hydrogenation of these the correspondi g noval androstoneand testane compounds. tion with sodium borohydride gave the novelandro/ genie 3-alcohols of both the A -compounds and the andiv mcompounds.

The noval androgenic hormones of the presen 5 i tion may therefore beexemplified by the f llqwing formulas:

ILX

Patent 0 Further I$ duc- 2,844,602 Patented July 22, 1958 In the aboveformulas R represents an alkyl or aralkyl group, preferably a loweralkyl group of less than 7 car- -bon atoms, such as methyl or ethyl, orthe benzyl group. R represents hydrogen or an acyl group of the typeconventionally found in esterified steroid alcohols, these arethosegenerally derived from hydrocarbon carboxyhe acids of less than 12carbon atoms such as acetlc, propionic, cyc lopentylpropionic, benzoicetc. R represents a lower alkyl group of less than 7 carbon atoms suchas methyl, ethyl or propyl. X represents a double bond between 0-4 andC-5 and a saturated linkage between (3-4 and 0-5.

The novel compounds of the present invention may be prepared by-aprocess exemplified in part by the following equation:

and

ethyl oxalate 0 sodium hydride O I o-OH l Rtodide brominatton reduc-/ hydrogenatlon icatalyst OH OH I I- a I TH HO i redne-/ /tion OK i L--. z

E0 I l H In'the above equation R represents hydrogen or is the same as Rpreviously referred to.

In practicing the process above outlined etiocholan;(testan)-17,3.-ol-3-one or its derivatives havinga 17alower alkylgroup, ,are dissolved in an organic solvent such as benzene and treatedwith ethyl oxalate and sodium hydride. The reaction mixture is stirredfor a period of time of the order of 4 hours and then treated withwater. The product upon acidification and separation from the aqueousphase was the corresponding 4-ethoxy-glyoxyl derivative.

The glyoxyl derivative was then dissolved in an organic solvent such asacetone and mixed with potassium carbonate and an alkyl or aralkyliodide, such as methyl, ethyl or benzyl iodide. After about 40 hoursunder reflux the product after concentration, partial purificationprocedure was the corresponding 4-alkyl or aralkyl-4-ethoxyglyoxyl-etiocholan-l75-o13-0ne derivative. The partially crudeproduct was then dissolved in a solution of sodium ethoxide in ethanoland the solution kept standing for about 18 hours at room temperature.Upon addition of water, extraction with an organic solvent andchromatography the corresponding 4-alkyl oraralkyletiocholan-l7fi-ol-3-one derivative was obtained.

These derivatives upon monobromination (with slightly over 1 molarequivalent of bromine) gave the corresponding 4-bromo compounds andupondehydrobromination with a tertiary amine such as collidine thecorresponding M-compounds were formed. These may be characterized ingeneral as..4:a1kyl -or aralkyl derivatives of testosterone or 4-alkylor arallcyl derivatives of 17alower alkyl testosterone. By conventionalacylationprocedures as by treatment with acid anhydrides there wasprepared the l7-esters of the 4-alkyl or aralkyl derivatives oftestosterone. These esters were those of hydrocarbon carboxylic acids ofless than about 12 carbon atoms.

The M-compounds upon hydrogenation in the presence of a hydrogenationcatalyst preferably a palladium catalyst gave a mixture of thecorresponding testane and androstane compounds.

iUpon reduction with sodium borohydride of either the A compounds or thecorresponding saturated derivatives the 3-keto group was transformedto a3-hydroxy group; a mixture of the 30: and 3B alcohols being found. Inthe case of compounds having a 17a-alky1 group conventional acylationgave 3-mono-esters of the type previouslyreferred to, in the case of theother 3-hydr0xy derivatives conventional acylation gave the3,17-diesters.

4 The following specific examples serve to illustrate but are notintended to limit the present invention.

Example I 2 g. of etiocholan-l7e-ol-3-one in 50 cc. of anhydrous benzenefree of thiophene was treated with 1 cc. of ethyl oxalate and 600 mg. ofsodium hydride. The mixture was stirred for 4 hours under an atmosphereof nitrogen, cooled and treated dropwise with water to decompose theexcess of hydride, followed by cc. more of water. The precipitated enol'salt was stirred, and the aqueous solution was separated from the sodiumsalt. Acidification of the aqeuous phase and extraction with methylenedichloride afiorded 2.1 g. of the 4-ethoxy-glyoxyl derivative.

2 g. of the above compound was dissolved in 100 cc. of anhydrousacetone, mixed with 1 g. of anhydrous potassium carbonate and 5 cc. ofmethyl iodide and the mixture was refluxed for 40 hours and thenconcentrated almost to dryness and diluted with 50 cc. of methylenedichloride. The mixture was extracted twice with 100 cc. portions of acold 1% solution of sodium hydroxide and the methylene chloride solutionwas separated and evaporated to dryness, thus producing 4 methyl 4'ethoxyglyoxyletiocholan-17fi-ol-3-one, which was used without furtherpurification for the next step.

The crude product obtained in the previous operation was dissolved inasolution of sodium ethoxide in ethanol (prepared by dissolving 1g. ofsodium metal in 50 cc. of anhydrous ethanol) and the solution was keptstanding for 18 hours at room temperature. 300 cc. of water was thenadded, the mixture was extracted with methylene dichloride and themethylene dichloride solution was evaporated to dryness. Chromatographyof the product on a column with 50 g. of neutral alumina yielded, uponelution with benzene, 600 mg. of 4-methyl-etiocholan-l713- ol-3-one.

500 mg. ofthis compound was dissolved in 100 cc. of glacial acetic acidcontaining one drop of a solution of hydrogen bromide in acetic acid andthen treated dropwise under continuous stirring with 1.1 molarequivalents oi bromine in 5 cc. of acetic acid at 15 C. The solution wasdiluted with water and the precipitate was collected to give SSO-mg. of4-bromo-4-methyl-etiocholan-l7B-ol- 3-one.

500 mg. of this compound was refluxed for 1 hour with 3 cc.\of'collidine. The cooled mixture was diluted with 20 cc. -of ethylacetate, the precipitated collidine hydrobromide was filtered and theethyl acetate solution was washed with dilute sulfuric acid and thenwith water until neutral. The solution was evaporated to dryness and theresidue was chromatographed on a column with 25 g. of alumina. Thefractions eluted with benzeneether (9:1) yielded 200 mg. of4-methyl-testosterone having a melting point of 169-171" C., [111 +121(chloroform).

Routine acetylation with acetic anhydride in pyridine solution alfordedthe acetate of 4-methyl-testosterone. By similar routine acetylationwith acid anhydrides and chlorides there was also prepared other estersof hydrocarbon carboxylic acids of less than 12 carbon atoms such as thepropionate, cyclopentylpropionate and benzoate.

Example 11 Following the method described in Example I, but using ethyliodide instead of methyl iodide, there was obtained 4-ethyl-testosteroneand its esters.

Example 111 Following the method described in Example I, but usingbenzyl iodide instead of methyl iodide, there was obtained4-benzyl-testosterone and its esters.

Example IV A solution of 50 g. of 17a-methyl-testosterone in 1 l.

of neutral alumina to separate the 17a-methyl-androstan- 17B-ol-3-onefrom 17a-methyl-etiocholan-17fl-o1-3-one.

2 g. of l7a-methyl-etiocholan-175-01-3-one was subjected to the sequenceof reactions described in Example I, thus giving 4,17a-dimefl1y1-A-androsten-17p-o1-3-one.

Example V Following the method described in Example IV, and startingfrom 17a-ethyl-testosterone, there was obtained 4-methyl-17a-ethyl-Aandrosten-17fl-ol-3-one.

Example VI Following the method described in Example v, but using ethyliodide instead of methyl iodide, there was obtained 4,l7a-diethyl-A-androsten-17,8-01-3-one.

Example VII By obvious variations to the methods described previously,there were prepared the following derivatives of testosterone:4-ethyl-17a-methyl, 4-methyl-l7a-propyl, 4- ethyl-l7a-propyl,4-benzyl-l7a-methyl, 4-benzyl-17a-ethyl and 4-benzyl-l7a-propyl.

Example VIII 1 g. of 4-methyl-testosterone in 50 cc. of methanol washydrogenated at room temperature and atmospheric pressure in thepresenceof a previously reduced 5% palladium on barium sulfate catalyst.In the course of 1 hour'the equivalent of 1 molar equivalent of hydrogenwas absorbed. The catalyst was filtered, the filtrate was evaporated todryness and the residue was chromatographed in a column with 100 g. ofneutral alumina, thus giving as a main fraction 4-methyl-androstan-17B-ol-3-one and as a secondary fraction4-methyl-etiocholan-17 6-01-3-one.

In the same way there were prepared 4-ethyl-androstan- 17fi-ol-3-one and4-benzyl-androstan-l7j3-ol-3-one.

From the above compounds there were prepared their 17-acetates byroutine acetylation with acetic anhydride in pyridine solution, at thetemperature of the steam bath. By similar routine acylation with acidanhydrides and chlorides there was also prepared other esters ofhydrocarbon carboxylic acids of less than 12 carbon atoms such as thepropionate, cyclopentylpropionate and benzoate.

Example IX 1 g. of 4,17a-dimethy1-testosterone, obtained in accordancewith Example IV, was treated as described in Exam-- Example l A solutionof l g. of 4-methyl-testosterone in 20 cc. of methanol was treated with100 mg. of sodium borohydride previously dissolved in 2 cc. of water andthe mixture was kept standing overnight at room temperature. The solventwas evaporated under reduced pressure, water and a few drops of aceticacid were added to the residue and the reaction product was filtered togive a mixture of 4-methyl-A -androsten-3a,17B-diol and 4- methyl-A-androsten-3p,17/3-diol whose separation was not attempted. In ananalogous way there were obtained the 4-ethyl and 4-benzyl derivatives.

From all of the compounds mentioned in this example, there were preparedtheir 3,17-diacetates by reaction with acetic anhydride in pyridinesolution at the temperature of the steam bath. By similar routineacylation with acid anhydrides and chlorides there was also preparedother esters of hydrocarbon carboxylic acids of less than 12 carbonatoms such as the propionate, cyclopentylpropionate and benzoate.

Example XI 4 g. of 4-methyl-androstan-l7B-ol-3-one was treated inaccordance with the method described in Example X, and there wasobtained a mixture of 4-methyl-androstane-3a, l7,B-diol and4-methyl-androstan-3B,l7B-diol.

In the same way there were obtained the 4-ethyl and 4-benzylderivatives. From all of the compounds mentioned in this example, therewere prepared their 3-monoacetates by reaction with acetic anhydride inpyridine I solution at the temperature of the steam bath. By similarroutine acylation with acid anhydrides and chlorides there was alsoprepared other esters of hydrocarbon carboxylic acids of less than 12carbon atoms such as the propionate, cyclopentylpropionate and benzoate.

Example XII The treatment of 4,l7a-dimethyl-testosterone by the methoddescribed in Example X afforded a mixture of 4,l7a-dirnethyl-A-androsten-3a,17fi-diol and 4,17a-dimethyl-A -androsten-3B,17,5-diol.

In the same Way there were obtained the following derivatives of A-androstene-3,l7fl-diol: 4-methyl-l7a-ethyl, 4-methyl-l7a-propyl,.4-ethyl-17a-methy1, 4,17a-diethyl, 4-ethyl-l7a-propyl,4-benzyl-l7a-methyl, 4-benzyl-17w ethyl and 4-benzyl-l7a-propyl.

From all of the compounds mentioned in this example, there were preparedtheir 3-monoacetates by reaction with acetic anhydride in pyridinesolution at the temperature of the steam bath.

Example XIII 1 g. of 4,l7a-dimethyl-androstan-l7/3-ol-3-one was treatedin accordance with the method described in Example X, thus yielding amixture of 4,17a-dimethylandrostane3a,l'7/3-diol and4,l7a-dimethyl-androstane- 35,17,8-dio1.

In the same way there can be prepared the following derivatives ofandrostan-3,l7fl-diol: 4-methyl-l7a-ethyl, 4-methyl-17a-propy1,4-ethyl-l7a-methyl, 4,17a-diethyl, 4-ethyl-17u-propyl,4-benzyl-l7a-methyl, 4-benzyl-l7aethyl and 4-benzyl-17a-propyl.

From all of the compounds mentioned in the present example, there wereprepared their 3-monoacetates by reaction with acetic anhydride inpyridine solution at the temperature of the steam bath. By similarroutine acylation with acid anhydrides and chlorides there was alsoprepared other esters of hydrocarbon carboxylic acids of less than 12carbon atoms such as the propionate, cyclopentylpropionate and benzoate.

We claim:

1. A process for the production of compounds selected 'from the groupconsisting of 4-alkyl-A -androsten--01- 3-one, 4-aralkyl-A-androsten-17fi-o1-3-one, 17 lower alkyl-4-alkyl-A -androstenl75-ol-3-one and 17 lower alkyl-4-aralkyl-A -androsten-17/3-ol-3-onecomprising condensing a compound selected from the group consisting ofetiocholan-l7fi-ol-3-one and 17-lower alkyl-etiocholan- 17B-ol-3-onewith ethyl oxalate in the presence of sodium hydride to form thecorresponding 4-ethoxyglyoxyl derivative, treating the last mentionedderivative with an iodide selected from the group consisting of alkyland aralkyl iodides to form the corresponding compound selected from thegroup consisting of the corresponding 4-alkyl-4'-ethoxyglyoxyl and4-aralkyl-4'-ethoxyglyoxyl derivatives, treating the last mentionedcompounds with sodium ethoxide to form a compound selected from thegroup consisting of the corresponding 4-alkyl and4-aralkyl-etiocholanolone derivatives, monobrominating anddehydrobrominating these last mentioned compounds.

2. A process for the production of a compound selected from the groupconsisting of 4-alkyl-androstan- 17,8-01-3-one, 4-aralkylandrostan-17B-ol-3-one, 17-lower alky1-4 alky1-androstan-l7;3-ol-3-oneand 17-lower alkyl- 4-aralkyl-androstan-l7fl-ol-3-one comprisinghydrogenating a corresponding A compound in'the presence of ahydrogenation catalyst.

3. A process for the productionnof a compound selected from the groupconsisting-of 4-alkyl-A -androsten-3,17fldiol, 4-aralkyl-A-androsten-3,17fi-diol, 17-lower alkyl-4- alkyl-A-androsten-3,l7/8-diol, l7-lower alkyl-4-aralkyl- A-androsten-3,l7,9-diol, 4'-,alkyl-androsten-3,l7fl-diol, 4-aralkyl-androsten-3,17,8:diol, 17-loweralkyl-4-alkyl-androstan-3,17fl-dio1, and 17-lowerakyl-4-aralkyl-androstan-3,17;3-diol which comprises treating thecorresponding B-ketone with sodiumborohydride.

4. The process of claim 1 wherein the iodide is selected from the groupconsisting of methyl, ethyl, or benzyl iodide and the 17-1ower alkylgroup is selected from the group consisting of methyl, ethyl and propyl.

5. The process of claim 2 wherein the iodide is selected from the groupconsisting of methyl, ethyl, or benzyl iodide and the l7-loweralkylgroup is selected from the group consisting of methyl, ethyl andpropyl.

V 6. The process of claim 3 wherein the iodide is selected from thegroup consisting, of methyl, ethyl, or benzyl iodide and the 17-loweralkyl group is selected from the group consisting of methyl, ethyl andpropyl.

7. A compound of the following formula wherein R is selected from thegroup consisting of alkyl and aralkyl, R represents lower alkyl, and Xis selected from the-'groupcon'sisting of a double bond-betWeen'C- land-C-VS anda'sat-urated linkage"between and 'C-5.

15. 17-lower alkyl 4-'- lower alkyl-M-androsteh-Ufiol-S' o'ne.

1 6. 17-lower one. A

17-; 4;17-dimethyl A -androsten-17fl-ol-3-one.-

1 *17-lower'alkyl 4 lower a1kyl-androstan-17 3-ol-3- l7 -lower'alkyl-4-benzyl-androstan-175-ol-3-one.-

. 4,17-'dimethyl androstaii-1713-ol 3-one. A compound of the followingformula:

wherein R'is selected from the group consisting of alkyl and aralkyl, Ris selected from the group consisting of hydrogen and acyl, and X isselectedfrom-the group con- OH l g:

wherein R is selected from the group consisting of alkyl and aralkyl, Ris selected from the group consisting-of hydrogen and acyl, Rrepresent's lower alkyl, and X is selected from the group consisting. ofa double. bond between C-4and C-5 and a saturated linkage between C-4andC SQ v 29. 17-lower alkyl-4-lower alkyl-A -audrosten-3J7p3- 30.17-lowerallryl-A-benzyl-M-androstem3,l7p-diol. 31. 4,17-ditnethyl-A-androsten-3,l7B-diol.

32. 17-1ower alkyl-A-lower alkyl-androstan-3,17p-diol. 33. '17-1oweralkyl-4-benzyl-androstal -3,17p-diol,

34. 4, 17-dimethy1-androstan-3 17 fi-diOl.

No references cited.

alkyl' 4 benzyl-A -androsten--01-3-

7. A COMPOUND OF THE FOLLOWING FORMULA
 21. A COMPOUND OF THE FOLLOWING FORMULA: 